Animal models of psychiatric disorders and their relevance to alcoholism.

Animal models are important tools in the study of psychiatric disorders, including alcoholism, because they allow the use of research methods that cannot be used for ethical reasons in humans. Consequently, scientists have developed numerous approaches to evaluate the validity and reliability of animal models for studying human behavior and human disorders. Researchers have developed animal models of schizophrenia, fear and anxiety, depression, and alcoholism, all of which are being used to study the relationship between alcoholism and co-occurring psychiatric disorders. These models may help researchers and clinicians determine how best to treat patients with alcoholism and co-occurring psychiatric disorders.

S cientists are increasingly being asked both to develop and to defend the use of animal models for studying p s ychiatric disorders that appear to be uniquely human, such as alcohol and other substance abuse, schizo p h re n i a , d e p ression, and anxiety. These disord e r s either are not observed in animals or cannot be directly measured (i.e., the animals cannot verbally indicate what they think or feel). This re v i ew examines some of the animal models used to study these disorders, with a special emphasis on the use of these models in the search for genes that contribute to the disord e r s .
The general argument for using animal models in behavioral re s e a rch is that such models allow re s e a rchers to test specific hypotheses under highly cont rolled conditions using methods that a re either impossible or unethical to use in humans. For example, re s e a rc h e r s can create genetically altered mice (e.g., mice with a foreign gene added to their genetic makeup) to examine the influence of specific gene products on behavior. Recent advances in genetic engineering a l l ow investigators to activate or inactivate specific genes in specific regions of the brain. Other re s e a rch techniques that scientists can only use in animals include injecting materials directly into the brain and implanting brain electro d e s .
Critics of animal models in behavioral re s e a rch have argued that these studies could be conducted using animals with simpler systems, such as worms, or computer simulations. This argument is based on the theory that the basic p rocesses that increase or decrease the s t rength of communication betwe e n and among cells (i.e., the synaptic connections), and there f o re influence b e h a v i o r, are probably similar in organisms as "s i m p l e" as the worm and as "c o m p l e x" as the human. In higher ve rtebrates, howe ve r, these basic pro c e s s e s combine into highly sophisticated and complex arrays that no computer system has yet been able to duplicate. Thus, t h roughout the foreseeable future ,

RO B E RT HI T Z E M A N N, PH. D . , is a pro f e ssor and chairman of the De p a rtment of Be h a v i o ral Ne u roscience, Oregon He a l t h Sciences Un i ve r s i t y, Po rtland, Ore g o n , and a re s e a rch pharmacologist at the Re s e a rch Se rvice, Ve t e rans Affairs Medical Ce n t e r, Po rtland, Ore g o n .
This re s e a rch was supported in part by Public Health Se rvice Gra n t s AA-11034 and MH 51372 and a gra n t f rom the De p a rtment of Ve t e rans Affairs.
re s e a rchers investigating complex behavi o r a l traits and characteristics (i.e., phenotypes) of humans will continue to be forced to use animals with we l ld e veloped central nervous systems rather than simpler organisms or computer models. Although rodents are not as a p p ropriate as are primates for modeling all aspects of a specific human behavior, rodents will carry the main workload of animal re s e a rch for some time to come. This article describes animal models of schizo p h renia, fear and anxiety, and d e p ression. It also discusses the use of animal models in studying alcoholism and co-occurring psychiatric disord e r s . First, howe ve r, validity and re l i a b i l i t ythe criteria used to evaluate animal m o d e l s -a re defined.

Criteria for Animal Models of Human Behavior
Validity and reliability are the main criteria for evaluating animal models (for a re v i ew, see Ge yer and Ma rkou 1995). This article first examines the four aspects of validity-face, pre d i c t i ve, etiological, and genetic-and then focuses on the issue of re l i a b i l i t y.
Face va l i d i t y refers to the similarity b e t ween the animal model and the specific human behavior of interest. Su p e rf i c i a l l y, it would seem that the animal behavior should mimic the related human behavior as much as possible. For examp l e , mouse and man display similar responses to a loud noise (i.e., s t a rt l e responses). Both respond with an e yeblink, a rapid change in heart rate, a n d some form of whole body move m e n t (e.g., a mouse jumps, a person jerk s ) . Howe ve r, when studying the re g u l a t i o n of the startle response, the observe d response need not be obviously similar. For inve s t i g a t i ve purposes, the re s u l t s would be just as informative if the mouse yawned or curled its tail, providing that these phenotypes could be re l i a b l y m e a s u red and had pre d i c t i ve, etiological, and genetic validity (described later in this art i c l e ) .
Re s e a rchers studying animal models of human psychiatric disorders are i n c reasingly examining intermediate phenotypes or endophenotypes (i.e., m a rkers that may indicate a susceptibility to a disorder). Endophenotypes generally a re not immediately visible, but they may contribute to the susceptibility to d e velop a particular behavior or synd rome. The use of endophenotypes is helpful in that the underlying neuro b iology (i.e., the mechanisms or mechanism by which the endophenotype i n c reases susceptibility) is fre q u e n t l y k n own and thus re s e a rchers have the a d vantage (i.e., in the case of genetic studies) of linking specific gene(s) that may influence the behavior with specific brain mechanisms. A disadva n t a g e of endophenotypes, howe ve r, is their lack of specificity. For example, pre p u l s e inhibition of the acoustic startle re s p o n s e ( A S R ) 2 s e rves as an operational measure , or endophenotype, for the deficits in the mechanisms that allow normal individuals to filter or block most of the sensory and cognitive stimuli that they re c e i ve (i.e., sensory gating abnormalities). Such abnormalities are often seen in schizo p h re n i a (see table 1). Howe ve r, whereas schizo p h re n i c s s h ow poor prepulse inhibition, deficits also a re seen in To u re t t e's syndrome, bedwetting incidents, and during the mens t rual cyc l e .
Fu rt h e r m o re, the popularity of endophenotypes may derive partly fro m the fact that they generally have face validity (i.e., a complex human behavior has been reduced to something that c a n be measured under similar conditions i n l a b o r a t o ry animals and humans). Howe ve r, as previously stated, face va l i d i t y for an endophenotype does not justify its use.
Pre d i c t i ve va l i d i t y refers to the extent that an animal model can allow a res e a rcher to make predictions about the human phenotype. In many cases, pred i c t i ve validity refers to how useful animal models are for predicting the efficacy and safety of drugs for treating psyc h i a t r i c d i s o rders. For example, new antipsychotic drugs we re screened for years by their ability to block (in ro d e n t s ) amphetamine-induced behaviors (e.g., i n c reased licking, gnawing, and chew i n g ) . This test was based on the hypothesis that because amphetamine incre a s e s l e vels of dopamine (a key brain chemical i n vo l ved in nerve cell communication) and psychosis is associated with incre a s e d l e vels of dopamine, drugs that block amphetamine-induced behavior would be effective as antipsyc h o t i c s .
Howe ve r, the drugs selected using this test also produced extra-pyramidal symptoms (EPS), such as dru g -i n d u c e d Pa rkinsonism. EPS was one of the major reasons that people did not comply with d rug treatment. This problem eve n t u a l l y led to the development of new atypical a n t i p s ychotic drugs (i.e., drugs that maintain antipsychotic efficacy but do not produce EPS). New drugs we re s c reened for a particular receptor profile (i.e., either high or low affinity for a particular receptor-that is, a pro t e i n that binds to a specific brain chemical, or neurotransmitter). Once these compounds we re identified, the amphetamine test was used to determine if the new compounds could block the dru ginduced behaviors by a novel mechanism. S c reens such as this led to the deve l o pment of a new generation of atypical a n t i p s ychotics (e.g., risperidone and o l a n ze p i n e ) .
Etiological va l i d i t y exists when one can determine-to the extent possible-that the mechanisms invo l ved in a behavior observed in the animal model are similar to those invo l ved in the associated human behavior. The degree of startle response is reduced when a brief "warning" stimulus precedes the startle-eliciting stimulus.
Rodents will c a r ry the main w o rkload of animal re s e a rch for some time to come.
mechanisms of behavior and then by testing the role of such mechanisms in human behavior. In coming ye a r s , h owe ve r, the re verse process pro b a b l y will also be increasingly used: re s e a rc h e r s will first examine the underlying mechanisms in humans and then examine animal models to determine whether similar mechanisms are at work . For example, in a group of normal human controls, Vo l k ow and colleagues (1999) found that human subjects with naturally low D 2 dopamine re c e p t o r density re p o rted a euphoric effect in response to an intravenous injection of methylphenidate (Ritalin ™ ). These data led Thanos and colleagues (1999) to investigate whether elevating D 2 receptor density in rats would re d u c e alcohol pre f e rence. An increased re c e ptor density was associated with re d u c e d alcohol pre f e rence. Thus, the re s e a rc h e r s would test the relationship betwe e n receptor density and drug pre f e re n c e under controlled laboratory conditions. Genetic va l i d i t y exists when the risk for a disease is known to have a similar genetic component in both humans and the animal model. At least 50 perc e n t of the risk for psychiatric disorders such as schizo p h renia, depression, and alcoholism can be attributed to inherited genetic factors. Thus, for any animal model of these disorders, it would be useful-but not necessary-to demonstrate a significant genetic component to the natural phenotypical va r i a t i o n . Various strategies can be used, with the e ventual goal of detecting re l e vant genes. Re s e a rchers have made considerable p ro g ress in this area for behavioral phenotypes (Crabbe et al. 1999), although results still lag behind the detection of genes for other complex phenotypes (e.g., diabetes, obesity, and hypert e nsion) (e.g., Pomp 1997).

Reliability of the Model
The reliability of the animal model refers to the stability and re p ro d u c i b i l i t y of the phenotype. Some animal phenotypes appear to show re m a rkable stability. For example, by using alcohol-induced locomotion as a measure of alcohol's acute stimulant re s p o n s e 3 in a series of i n b red mouse strains (De m a rest et al. 1999), we obtained results essentially identical to those obtained by Cr a b b e and colleagues (1983).
Stability of the phenotype also can refer to test-retest re l i a b i l i t y, a constru c t f requently used in studies on humans. Scientists working with animals, howe ve r, have been reluctant to use a testretest design; arguing-and fre q u e n t l y demonstrating-that the first test will significantly affect the second test. When w o rking with inbred (i.e., geneti c a l l y identical) animal strains, the extent t o which this is a problem can be measu red easily by comparing animals tested once with animals tested multiple times. Howe ve r, when using genetically segregating populations (i.e., in which each individual is genetically unique), such a solution is not possible. In order to make a sound decision, re s e a rchers must weigh the advantages and disadva n t a g e s of repeatedly testing animals. Be c a u s e the main effect of poor test-retest re l i ability is to decrease statistical powe r, i n c reasing sample size and testing only once is a solution to the pro b l e m .

Suitability of the Animal Species for a Specific Experimental Need
Hi s t o r i c a l l y, behavioral studies have largely relied on the use of the albino o u t b red rat (i.e., each animal is genetically unique) as the primary experimental species. For genetic studies, howe ve r, mice offer advantages over rats, such as the availability of numerous inbre d mouse strains, animals in which genes h a ve been added or deleted (i.e., transgenic animals), and a we l l -d e s c r i b e d genome. When rat paradigms are adapted to the mouse, especially paradigms i n volving higher order learning, mice tend to do poorly (Crawley et al. 1997). Whether or not this difference re f l e c t s a difference in "intelligence" or the need for new protocols specifically suited to the mouse's abilities and temperament is unclear.
Mice present other disadvantages to re s e a rchers as well. For example, re s e a rchers frequently encounter mark e d s e n s o ry deficits when using inbred mouse strains. Nu m e rous strains, including some of those most frequently used (e.g., DBA/2J, C57BL/6J, and BALB/cJ) h a ve marked high frequency hearing deficits, which in the DBA/2J can be detected as early as 4 to 6 weeks of age. Other strains (e.g., the C3H/HeJ) show m a rked retinal degeneration at an early age. Obv i o u s l y, such animals would be unsuitable for tests that re q u i re the animal to remember spatial cues. In addition, albino rats and mice show impaire d vision under bright lights, which they a re exposed to in the standard open-field test (see table 1), a deficit that must be accounted for when interpreting their p e rformance. Although the ava i l a b i l i t y of transgenic mice is an advantage for re s e a rch, this technology presents disa d vantages as well (see the article in this issue by Bowers, pp. 175-184).

Models of Psychiatric Disorders
In vestigators use animal models to study the mechanisms invo l ved in seve r a l p s ychiatric disorders and to inve s t i g a t e the relationship between alcoholism and co-occurring disorders. This section describes animal models for schizo p h ren i a , d e p ression, and fear and anxiety. The use of animal models to study a l c o h o l i s m and co-occurring psyc h i a t r i c d i s o rd e r s is discussed in the subsequent section.

Schizophrenia
S c h i zo p h renia is one of the most disabling of all psychiatric disorders. The lifetime risk of developing schizo p h re n i a is approximately 1 percent, a risk rate that appears to be largely independent of race, culture, and socioeconomic status. Schizo p h renia is characterized by both positive symptoms (e.g., delusions, hallucinations, and thought disord e r ) and negative symptoms (e.g., withdrawal and a dementia-like state). In addition, the mechanisms of schizo p h renia appear to be highly diverse. Gi ven this level of c o m p l e x i t y, the difficulty in deve l o p i n g an animal model that can capture the s c h i zo p h renic pathology is appare n t . Pro g ress has been made in this effort ,

Behavior Modeled Phenotype Description
Both the ASR and TSR measure startle reactivity and, in general, show a good correlation to each other. The ASR is elicited with a loud noise; the TSR is generally elicited with an air puff. The response (reflex) is measured by coup l i n g the startle platform to a strain gauge transducer or some similar device.
In humans, the startle response is generally measured by the strength of the eye-blink reflex. Habituation to the startle response is abnormal in schizophrenia.
PPI refers to a reduction in the startle response that is observed when a brief (e.g., 20 millisecond) sensory stimulus (the prepulse stimulus) is delivered prior (100 to 1000 milliseconds) to the stimulus that induces the ASR or TSR. The prepulse stimulus inhibits the magnitude of the ASR or TSR. The prepulse can be different from the startle stimulus. In general, treatments that increase brain dopaminergic activity decrease PPI. PPI is reduced in schizophrenia.
H o w e v e r, any disorder (e.g., drug abuse) that is likely to involve brain dopamine systems is a candidate to affect PPI.
LI refers to the inhibition of a conditioned response (e.g., avoidance of a shock) caused by preexposure to the conditioned stimulus (CS) (e.g., a loud tone). The preexposure phase consists of random exposure to a CS. In the test phase, the CS is presented with an aversive unconditioned stimulus (US) (e.g., a scrambled footshock). Preexposure to the CS delays acquisition of the conditioned avoidance response. Numerous human paradigms are available for measuring LI. LI is reported to be abnormal in schizophrenics (i.e., they more quickly make the CS-US association). In general, the animal data suggest that PPI and LI are measuring different processes.
In a typical FPS paradigm, the degree of conditioned fear is reflected by the increased amplitude of the ASR or TSR elicited in the presence of a CS previously paired with an aversive US. In humans, the ASR is enhanced both in anticipation of aversive shock and in association with certain disorders (e.g., posttraumatic stress disorder).
Contextual fear conditioning is measured by noting the change in locomotor activity (generally bouts of freezing in place) when the animal is placed in the chamber where the CS was paired with an aversive US.
Cued fear conditioning is conceptually similar to FPS. Rather than measuring the change in ASR, the change in locomotor activity is measured after presentation of the CS.

Behavior Modeled Phenotype Description
The light-dark transition test forces the animal to make a choice between explori n g the brightly lit area of the open field or staying in the dark area (the natural tendency). Anxiety-reducing drugs increase exploration in the bright area.
The elevated plus maze is similar in concept to the light-dark test except that the animal must choose between exploring a novel environment and the tendency to escape from the elevated open arms of the maze. This is one of the earliest models using drugs to mimic a psychiatric disorder. It is based on the clinical observation that 10 to 20 percent of patients administered reserpine (generally for hypertension) report symptoms of depression. In rodents, moderate doses of reserpine induce locomotor depression. The model is no longer used.
Learned helplessness refers to a variety of paradigms in which the animal is exposed to an inescapable aversive stimulus (e.g., a foot shock). Eventually, a certain proportion of the animals will give up and make no attempt to escape. The model has numerous problems but does show predictive validity in that antidepressants and electroconvulsive shock reverse the learned helplessness in susceptible animals.
Conceptually, behavioral despair is related to learned helplessness. In the typical test, the mouse or rat is forced to swim in a tank from which it cannot escape. At the outset, the animals swim vigorously; however, over time some of the animals become immobile, a condition Porsalt (1981) termed behavioral despair.
This model builds from the repeated observation that the chronic administration of central nervous system stimulants can induce paranoid psychosis. In animals, chronic stimulant administration will generally induce sensitization to some behaviors (e.g., stereotyped activity) and habituation to others (e.g., exploratory activity).
Clinically, drugs that act by blocking NMDA receptors (i.e., NMDA receptor antagonists), such as phencyclidine (PCP), ketamine, and dizoclipine induce temporary psychotic symptoms and cognitive disturbances somewhat mimicking the negative symptoms of schizophrenia. In animals, the effect of these drugs is generally measured by the temporary increase in locomotor activity.
Similar in concept to the NMDA receptor antagonist model, this model generally refers to drugs, such as LSD and mescaline, that induce hallucinations, particularly visual hallucinations. Although visual hallucinations are uncommon in schizophrenia and related psychotic disorders, understanding this relatively rare phenotype would be of value. Animal models generally focus on acute drug administration; response is measured as changes in locomotor activity or behavioral disruption. and a few of the approaches used are described here . S c h i zo p h renia is characterized by deficits in attention-related pro c e s s e s , information processing, and the sensing and filtering (i.e., sensorimotor gating) of environmental stimuli (Braff 1993). Prepulse inhibition of the acoustic startle response (described in table 1) has been used to measure the deficits in sensorimotor gating associated with s c h i zo p h renia. The data obtained led to increased interest in the related animal model, an approach that has seve r a l a d vantages. Me a s u rements of pre p u l s e inhibition are easily adapted to mice and rats, and the underlying mechanisms regulating prepulse inhibition appear to be similar, if not identical, in animals and humans. Antipsyc h o t i c d rugs improve poor prepulse inhibition, and dopamine agonists (i.e., compounds that combine with dopamine receptors) decrease prepulse inhibition. Fi n a l l y, the regulation of prepulse inhibition in animals is markedly influenced by genetic factors. Thus, prepulse inhibition has face, pre d i c t i ve, constru c t , and genetic va l i d i t y.
In addition to prepulse inhibition, poor latent inhibition is also associated with schizo p h renia (Braff 1993) and can be easily measured in animals. Latent inhibition refers to the inhibition of a conditioned response as a result of pree x p o s u re to the conditioned stimulus. In our laboratory, we have measure d latent inhibition in mice as follows. Mi c e we re randomly divided into two gro u p s . One group was given 50 trials, each consisting of a 10-second conditioning stimulus (CS) (i.e., a 2,000 hertz, 85 decibel tone); each trial was separated by 5 to 75 seconds. The second gro u p (i.e., the control group) did not re c e i ve the auditory CS. On the second day, both groups we re assessed for the acquis i t i o n of a conditioned avoidance re s p o n s e (CAR) in which the CS was associated with a mild footshock. Success on the test was measured by how quickly the animals learned to avoid the mild shock. Latent inhibition was observed in the p reexposed group (i.e., they acquire d the CAR more slow l y ) .
Considerable evidence suggests that dopamine has a re g u l a t o ry role in both p repulse inhibition of the acoustic s t a rtle response and latent inhibition ( re v i ewed in Kline and colleagues 1998). These data led us to investigate pre p u l s e inhibition and latent inhibition in lines of mice that had been selectively bre d to respond or not respond to the dru g haloperidol, a typical antipsyc h o t i c (also termed neuroleptic). Catalepsy, the mouse equivalent to extra pyramidal symptoms, was used to measure response to the drug (see table 1). Tw o lines we re created, neuroleptic re s p o n s i ve (NR) and neuroleptic nonre s p o n s i ve (NNR), which differ about twentyfold in their sensitivity to haloperidol. Nu m e ro u s d i f f e rences have been observed in brain dopamine systems between the NR and NNR lines, including the number of dopamine neurons and the density of D 2 dopamine receptors (Hi t ze m a n n et al. 1995).
Gi ven these differences, unsurprisi n g l y, Kline and colleagues (1998) found marked deficits in both pre p u l s e inhibition and latent inhibition in the NNR mice when compared with the NR line. From these data, we can conclude the following, at least in mice: (1) some of the same genes re g u l a t i n g the catalepsy response also regulate prepulse inhibition and latent inhibition, and (2) elucidating these genes will likely be important to understanding the underlying mechanisms of these behaviors. The question of whether or not such studies will illuminate schizo p h re n i c pathology remains unclear. Howe ve r, the information obtained provides new s t a rting points for future inve s t i g a t i o n ss t a rting points that would not have been possible without the use of animal studies.
In addition to the endophenotype a p p roach, re s e a rchers have used other strategies to model aspects of schizo p h ren i a, including administering hallucinogens and acute and chronic administration of stimulants (e.g., amphetamine). A number of problems occur with these a p p roaches (see Ge yer and Ma rk o u 1995). Because hallucinations cannot be observed in mice and rats, re s e a rc h e r s h a ve used endpoints, such as behavioral d i s ruption or locomotor stimulation (many hallucinogens are also stimulants). Fu rt h e r m o re, the hallucinations induced by drugs like LSD are primarily visual, w h e reas those seen in schizo p h renia are m o re likely to be auditory or olfactory.
Stimulant models of psychosis aro s e after re p o rts that stimulant abuse re s u l t e d in paranoid delusions. Re s e a rchers conducted controlled chronic administration studies to demonstrate that the paranoia was not associated with a preexisting psychiatric disorder but re s u l t e d f rom a maladaptive drug response. The c h ronic administration of stimulants to most strains of rats and to some strains of mice leads to drug sensitization (i.e., i n c reased sensitivity) characterized by an increase in certain behaviors (e.g., patterned locomotion, highly re p e t i t i ve g rooming, and gnawing and licking m ovements). Thus, re s e a rchers deve l o p e d an animal model in which incre a s e d motor responses substituted for the paranoid delusions observed clinically. Despite the lack of face va l i d i t y, the argument was made that the model was likely to have etiological va l i d i t y. Fu rt h e r m o re, the stimulant sensitization model both developed from and added to the hypothesis that psyc h o s i s is related to excesses in dopamine activi t y. In recent years, re s e a rchers inve s t igating psychosis and schizo p h re n i a h a ve favo red other theories over the dopamine hypothesis. Howe ve r, the sensitization model has been adopted by alcohol and other drug abuse re s e a rc h e r s to investigate the adaptive and pathological effects of chronic intox i c a t i o n . The validity and heuristic value of this a p p roach is detailed in this issue and in volume 24, number 2.

Alcohol Research & Health
The sensitization model has been adopted by alcohol and other drug abuse re s e a rc h e r s to i n vestigate the adaptive and pathological effects of chronic intox i c a t i o n .
Another approach to modeling s c h i zo p h renia, which has elements of both the hallucinogen and stimulant strategies, examines drugs that act by blocking receptors for N-m e t h y l -Da s p a rtate (NMDA) (i.e., NMDA antago n i s t s ) , such as phencyclidine (PCP), ketamine, and MK-801. Soon after the introduction of PCP in the 1950s, re s e a rchers re c o g n i zed that the dru g could produce both positive and negative symptoms of schizo p h renia in normal c o n t rol subjects and intensify psyc h o t i c symptoms in chronic schizo p h re n i c s . Animal models developed from these o b s e rvations have largely focused on NMDA antagonist-induced incre a s e s in locomotor activity and disruption of s e n s o ry gating (e.g., prepulse inhibition of the acoustic startle response) (Ge ye r and Ma rkou 1995).

Depression
De p ression is a common disorder (i.e., the lifetime pre valence is 15 to 25 percent) and is frequently encountered both in the psychiatric clinic and the primary c a re setting. In addition to symptoms such as depressed mood, failing to find p l e a s u re from normally pleasurable activities, and feelings of wort h l e s s n e s s and guilt, typical depression is charact e r i zed by a number of ve g e t a t i ve signs, including slowed activity, insomnia (or hypersomnia), and weight loss (or gain).
One of the earliest models of d e p ression was built from the clinical o b s e rvation that more than 10 perc e n t of patients taking the antihypert e n s i o n d rug reserpine develop some symptoms of depression. In animals, reserpine causes locomotor depression. The observa t i o n that the locomotor depression could be re versed by 5-hyd rox y t ry p t o p h a n (5-HTP) (a precursor to serotonin) or d i h yd roxyphenylserine (DOPS) (a precursor of nore p i n e p h r i n e ) led to the d e velopment of the theory that depre ssion occurred as a result of a d e f i c i e n c y in serotonin or nore p i n e p h r i n e (a theory that has changed little in more than 40 years). Re s e a rchers have expanded the t h e o ry based on the observations that inhibitors of the enzyme cholinesterase caused clinical symptoms of d e p re s s i o n and psychomotor depre s s i o n in animals.
Thus, depression was thought to deve l o p f rom an imbalance between high choline r g ic activity on one side and low serotonergic or noradrenergic activity on the other.
Learned helplessness and the re l a t e d phenotypes of behavioral despair and c h ronic unpredictable stress have been used to model some aspects of depre ssion. Ma rtin Seligman originally deve loped the learned helplessness model by exposing dogs to shocks from which they could not escape. The dogs eve n t u a l l y g a ve up and made no effort to escape the shocks (i.e., they became helpless). In addition, other behaviors we re affected (e.g., the dogs appeared apathetic and had poor appetites).
The importance of the learned helplessness model in understanding the pathology of depression builds from the argument that helplessness is a common characteristic of depression and that d e p ression can improve if the clinician instills in the patient a sense of mastery and control over the environment. Rather than debating the value of this model (if any) to understanding depre s s i o n , we will discuss the observance of learned helplessness in animals. The model has s e veral problems. For example, only a re l a t i vely small pro p o rtion of the animals exposed to the inescapable shock become truly helpless. Among outbre d stocks of rats, such as the Sp r a g u e -Da w l e y or Wi s t a r, only 10 to 50 percent deve l o p the helplessness syndrome (Wi l l n e r 1991). The low incidence may be attributable to genetic factors, but the data also suggest that the phenomenon is not a common adaptive mechanism. Fu rt h e r m o re, among inbred strains of mice, some will exhibit helplessness in the absence of training (i.e., the B6 mouse fre ezes in response to shock and does not attempt to escape). These data suggest that some of the differe n c e s b e t ween helpless and nonhelpless animals may relate to natural differences in the pattern of motor responses. Fu rt h e r m o re , other investigators have emphasized the difficulty in unraveling helplessness fro m a shock-induced reduction in motor activity (see Willner 1991), which is commonly seen in rodents in re s p o n s e to any chronic unpredictable stre s s (e.g., crowding, irregular feeding, and i n t e r rupted sleep). In contrast with these concerns, the model has had re asonably good pre d i c t i ve validity from a p s ychopharmacological perspective; a wide variety of antidepressants and e l e c t ro c o n v u l s i ve shocks reduce the helpless behavior.
Behavioral despair is related conceptually to learned helplessness. In this model, re s e a rchers forced rodents to swim in a tank from which they could not escape. At the outset, both the mice and rats swam vigoro u s l y. Over time, h owe ve r, the animals become immobile, a condition Porsalt (1981) called behavioral despair. The underlying constru c t validity of this model was questionable (e.g., the immobility could simply have been an efficient coping strategy). Howe ve r, the model had high pre d i c t i ve validity in identifying antidepre s s a n t s , especially after chronic administration (Willner 1991). Thus, the swim test and modifications of it (e.g., coupling the test with chronic unpredictable stre s s ) we re well-used models.

Fear and Anxiety
Both fear and anxiety are alerting signals that warn the individual against impending danger and enable the individual to take defensive measures. For animals, the distinctions between fear and anxiety are vague. For the purposes of this discussion, the animal models are divided into those that measure conditioned fear (i.e., fear that is learned by association with an ave r s i ve stimulus) and unconditioned fear (i.e., fear that is f rom two sources. One, alcoholism will need to be defined into ever more rigo rous and homogeneous phenotypes and the new classifications will need to include informative and easily measure d endophenotypes. Two, scientists work i n g with animals will need to be vigoro u s in building new models that incorporate the new clinical classifications but at the same time maintain ethological p e r s p e c t i ve. s